Spinocerebellar ataxia type 7 (SCA7) is a dominantly inherited
neurodegenerative disorder caused by a CAG -
polyglutamine (
polyQ) repeat expansion in the
ataxin-7 gene. In
polyQ disorders, synaptic dysfunction and neurodegeneration may develop prior to symptom onset. However, conditional expression studies of
polyQ disease models demonstrate that suppression of gene expression can yield complete reversal of established behavioral abnormalities. To determine if SCA7 neurological and neurodegenerative phenotypes are reversible, we crossed PrP-floxed-SCA7-92Q BAC transgenic mice with a
tamoxifen-inducible
Cre recombinase transgenic line, CAGGS-Cre-ER™. PrP-floxed-SCA7-92Q BAC;CAGGS-Cre-ER™ bigenic mice were treated with a single dose of
tamoxifen 1 month after the onset of detectable
ataxia, which resulted in ~50% reduction of polyQ-ataxin-7 expression.
Tamoxifen treatment halted or reversed SCA7 motor symptoms, reduced
ataxin-7 aggregation in Purkinje cells (PCs), and prevented loss of climbing fiber (CF)-PC synapses in comparison to vehicle-treated bigenic animals and
tamoxifen-treated PrP-floxed-SCA7-92Q BAC single transgenic mice. Despite this phenotype rescue, reduced
ataxin-7 expression did not result in full recovery of cerebellar molecular layer thickness or prevent Bergmann glia degeneration. These results demonstrate that suppression of mutant gene expression by only 50% in a
polyQ disease model can have a significant impact on disease phenotypes, even when initiated after the onset of detectable behavioral deficits. The findings reported here are consistent with the emerging view that
therapies aimed at reducing neurotoxic gene expression hold the potential to halt or reverse
disease progression in afflicted patients, even after the onset of neurological disability.